An update on the cognitive impact of clinically-used hormone therapies in the female rat: Models, mazes, and mechanisms

doi:10.1016/j.brainres.2013.01.016

Brain Research

Volume 1514, 13 June 2013, Pages 18-39

https://doi.org/10.1016/j.brainres.2013.01.016 Get rights and content

Abstract

In women, ovarian hormone loss associated with menopause has been related to cognitive decline. Hormone therapy (HT) may ameliorate some of these changes. Understanding the cognitive impact of female steroids, including estrogens, progestogens, and androgens, is key to discovering treatments that promote brain health in women. The preclinical literature has presented elegant and methodical experiments allowing a better understanding of parameters driving the cognitive consequences of ovarian hormone loss and HT. Animal models have been a valuable tool in this regard, and will be vital to future discoveries. Here, we provide an update on the literature evaluating the impact of female steroid hormones on cognition, and the putative mechanisms mediating these effects. We focus on preclinical work that was done with an eye toward clinical realities. Parameters that govern the cognitive efficacy of HT, from what we know thus far, include but are not limited to: type, dose, duration, and route of HT, age at HT initiation, timing of HT relative to ovarian hormone loss, memory type examined, menopause history, and hormone receptor status. Researchers have identified intricate relationships between some of these factors by studying their individual effects on cognition. As of late, there is increased focus on studying interactions between these variables as well as multiple hormone types when administered concomitantly. This is key to translating preclinical data to the clinic, wherein women typically have concurrent exposure to endogenous ovarian hormones as well as exogenous combination HTs, which include both estrogens and progestins. Gains in understanding the parameters of HT effects on cognition provide exciting novel avenues that can inform clinical treatments, eventually expanding the window of opportunity to optimally enhance cognition and brain health in aging women.

This article is part of a Special Issue entitled Hormone Therapy.

Section snippets

Ovarian hormones and cognition in the rodent: Historical context and clinical Implications

In 1927, A.S. Parkes published a monograph in The Proceedings of the Royal Society of Medicine entitled “Internal Secretions of the Ovary”, in which it is stated that, “The solution of the type of problem found in studying the internal secretions of the ovary is most satisfactorily sought by experiment, and since the lower mammals have to be used for this type of work, it is on their reactions that our knowledge of ovarian activity mainly depends. At the same time, however, ovarian activity in

Operationally defining and testing memory effects of female steroids in the preclinical setting

When studying learning and memory in the rodent model, it is vital to acknowledge the multiple parameters involved in the process of quantifying cognition in order to properly interpret data. Within the specific domain of spatial navigation, rodents learn to navigate through a novel environment so that routes to the target eventually become familiar, and associations are formed from cues in the environment to aid overall navigation. Spatial learning and memory involves the ability to navigate

Activational versus organizational effects of hormones: Perspectives for discussion herein

Gonadal steroid hormone actions are traditionally referred to as having organizational effects, operationally defined in the traditional sense as occurring early in development and having permanence, or as having activational effects which occur later in development, are transitory, and therefore depend on presence of the hormone at the time of assessment. For example, sex differences in neuroanatomy have been traditionally thought to reflect the permanent organizing effects of steroids present

Menopause etiology

Studies have shown that ovarian hormone loss negatively impacts cognition in women, and that these effects correspond to the associated estrogen deficiency (Farrag et al., 2002, Phillips and Sherwin, 1992, Sherwin, 1988). Others have shown modest, but statistically significant, declines in cognitive performance in women after surgical menopause, but express that the effects were small and not likely to be of clinical significance (Kritz-Silverstein and Barrett-Connor, 2002). In numerous

Estrogens

Estrogens are a class of hormones including 17β-estradiol, estrone, and estriol. 17β-estradiol is the most potent naturally-circulating estrogen, followed by estrone and estriol, in order of receptor affinity (Kuhl, 2005, Sitruk-Ware, 2002). Since the first controlled clinical evaluation showing that 17β-estradiol injections enhanced memory in 75 year-old women (Caldwell and Watson, 1952), numerous studies have demonstrated cognitive decline after ovarian hormone loss, and enhancement after

Progestogens

Progestogens include steroids with a pregnane skeleton, including naturally-occurring progesterone as well as progestins (synthetic progesterones). Inherent to any discussion on the impact of HT on cognition and the complexities involved in outcome, is that of combination therapy, which includes estrogen plus a progestogen concomitantly. Investigating combination therapy is crucial since women with a uterus taking estrogens must include a progestogen in their regimen to offset the increased

Androgens

Androgens are typically thought of as a “male” hormone; a masculinizing hormone which initiates permanent organizational effects on the male brain during a specific critical period in early development, and an activating hormone for male sex behaviors in adulthood. Why study androgens in females as a potential modulator of learning and memory? From our perspective, studying the impact of androgens on cognition in the female rodent model is important for several reasons. First, androgens bind to

Gonadotropins

Although it is well established that the gonadotropins (peptide hormones released from the anterior pituitary) follicle stimulating hormone (FSH) and lutenizing hormone (LH) are involved in regulating reproductive functions via negative and positive feedback loops, increasing evidence is indicating that gonadotropins, directly or indirectly, impact cognitive function as well, including within the spatial domain. Although the links between FSH and cognition do not appear to be realized (e.g.,

Cholinergic and γ-aminobutyric acid (GABA)ergic systems

Abundant evidence suggests that the cholinergic and GABAergic systems are intimately related to the effects of female steroids on cognition. Pharmacological experiments using both peripheral and intracranial infusions show that the cholinergic system may mediate estrogen-induced effects. Much of the landmark work evaluating relations between estrogens and the cholinergic system has been done via the creative and methodical approach of combining hormones and pharmaceutical agents in the

Hormone receptors and the cognitive effects of hormones

The cognitive effects of steroid hormones discussed thus far are, in part, mediated by distinct expression of receptors in the brain. Since its discovery in 1966, estrogen receptor-alpha (ERα) was the first, and thought to be the only, member of the nuclear receptor superfamily that exhibites specificity for 17β-estradiol (Toft and Gorski, 1966). It was not until 30 years later that the second ER subtype, ERβ, was discovered (Kuiper et al., 1996). The two ERs share a significant degree of

General conclusions

Gonadal hormones have activational effects on cognition. Interest in elucidating the factors that mediate these effects has intensified over the last decade. Notably, this heightened interest is within the realm of both the depth and breadth of the impact that ovarian hormones might exert on cognition. Of these effects, the significance of age-related cognitive decline, and how it may be exacerbated by concurrent gonadal hormone loss, has been an increasingly prominent area of focus in female